Immune checkpoint inhibitors (ICIs) have been transformative in the treatment of certain cancers, but as use of the drugs continues to climb, so do the ranks of patients dealing with gastrointestinal (GI) side effects.

GI adverse events, including inflammatory conditions of the colon, liver, stomach, pancreas, and gallbladder, affect up to 40% of patients on ICIs. They’re also among the most common grade 3 or higher adverse events experienced with the drugs.

“This underlies the importance of setting expectations and educating the patient,” said Saurin Chokshi, MD, of The University of Tennessee Health Science Center in Memphis, Tennessee.

Chokshi, who recently gave a talk on ICI-related GI toxicity at the National Comprehensive Cancer Network annual conference, spoke with Medscape Medical News about several critical points: The risk for severe events varies widely according to ICI type, it can take weeks or years for toxicities to arise, and certain risk-reduction steps are worth considering.

The following Q&A has been edited for length and clarity.

How do ICI-associated GI toxicities usually present?

The clinical presentation typically includes watery diarrhea, cramping, urgency, and abdominal pain. Red flags include blood and mucus in the stool, fever, and nocturnal symptoms. These suggest more severe disease requiring urgent evaluation.

The severity of these events varies considerably. While most cases are mild, severe enterocolitis occurs in 2%-5% of patients using PD-1 or PD-L1 inhibitors and in approximately 10% of those receiving cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitors. Other GI toxicities also include hepatitis, gastritis, pancreatitis, and cholecystitis.

Based on data from the FDA Adverse Event Reporting System (FAERS) for 2025, GI events constitute 20% of all reported immune-related adverse events. Immune-mediated colitis accounts for nearly 14% of events and carries a mortality rate of 16%. Intestinal perforation, while rare at about 1%, represents a life-threatening complication we must remain vigilant for.

At what point during treatment do GI toxicities typically appear?

The median time to onset is about 6 weeks, but there’s enormous variability. Symptoms can appear as early as 1 week or as late as 2 years after starting therapy. Critically, symptoms can occur or recur months after discontinuing the ICI. So maintain vigilance even in patients who’ve stopped treatment.

Can you talk more about the specific GI toxicities associated with different ICIs?

The risk for GI toxicity varies dramatically by ICI class.

Anti-CTLA-4 antibodies, particularly ipilimumab and tremelimumab, carry the highest risk, with diarrhea rates of up to 54%. They also exhibit the strongest association with immune-mediated enterocolitis in real-world pharmacovigilance data.

In contrast, the incidence of all-grade diarrhea with anti-PD-1 monotherapy is approximately 10%, while that of colitis is 2%, with no clinically relevant differences among pembrolizumab, nivolumab, and cemiplimab. Nivolumab has the highest risk for enterocolitis.

Among anti-PD-L1 inhibitors, durvalumab and atezolizumab have lower but still notable associations with enterocolitis. The 2025 FAERS analysis found durvalumab had the lowest proportion of GI adverse events among commonly used ICIs.

Predictably, combination therapy has the highest rates of immune-related adverse events. Ipilimumab combined with nivolumab produces diarrhea in 21%-37% of patients and colitis in 4%-8%, depending on the regimen.

Are there any patient-level risk factors that make these toxicities more likely?

Yes, some risk factors may affect the development of GI toxicities. One is tumor type. Some evidence suggests a higher incidence in patients with melanoma, though this may be confounded by the treatment regimen used.

Age and sex are also associated with risk. GI adverse events are most commonly reported in patients older than 65 years, although a significant portion do occur in younger patients. GI adverse events are also more common in men, except for pembrolizumab, where women have a higher rate of events.

Some additional risk factors include baseline gut microbiota composition and preexisting autoimmune disorders such as inflammatory bowel disease.

How are GI toxicities managed?

Management is grade-based: Use steroids as the first-line choice for grade 2 and above adverse events but don’t hesitate to escalate early to biologics for grade 3 or 4 events. Choose between infliximab and vedolizumab based on the patient’s underlying malignancy and comorbidities.

Immunotherapy rechallenge is possible after grade 2 event resolution, but after a grade 3 event, consider monotherapy only. Most importantly, maintain a high index of suspicion for these toxicities even after patients have stopped their ICIs.

Are there any preventive approaches for patients at increased risk for GI toxicities?

No proven pharmacologic prophylaxis currently exists to prevent ICI-induced GI toxicity. A randomized controlled trial indicated that prophylactic budesonide is not effective in preventing immunotherapy-associated enterocolitis. However, several risk-reduction strategies and emerging approaches merit consideration. These include:

• Assessing nonsteroidal anti-inflammatory drug (NSAID) use. NSAIDs have been associated with an increased risk for ICI-induced enterocolitis, so care should be taken to minimize or avoid these medications when possible.
• Proton pump inhibitor (PPI) review. PPI are associated with microscopic colitis and should be discontinued when not clearly indicated. Consider switching to an H2-receptor antagonist.
• Antibiotic stewardship. Antibiotics should be avoided before ICI initiation whenever possible because they can disrupt the gut microbiome and have been associated with worse outcomes. Consider temporarily delaying nonurgent immunotherapy if the patient has received broad-spectrum antibiotics within 1 month of planned treatment.

Are there any dietary modifications or other steps patients could take to lessen the risk for GI toxicities?

High-fiber diets (more than 20-30 g of fiber per day) have been associated with improved ICI response and may support a healthier gut microbiome. Aiming for 30 or more plant types weekly and minimizing animal meat intake may be beneficial.

Fermented foods may also have a beneficial effect on the gut microbiome and should be introduced where possible. Ideally, all patients should be referred to a nutritionist or dietician with knowledge of the gut microbiome before commencing ICI therapy.

Chokshi had no relevant financial disclosures.